The recent isolation and identification of enkephalin or morphine like factor from the brain has opened new possibilities for experimentation into the elucidation of mechanisms of pain and its alleviation by narcotic analgesics. Preliminary work has shown that the structure methionine-enkephalin in solution has many similarities to the morphine molecule. One of us (Dr. Freer) has synthesized a number of biologically active polypeptides including the two pentapeptides contained in enkephalin. We now propose to synthesize analogues of these natural occurring pentapeptides and study the structure activity relationship of these compounds and their ability to interact with opiate receptors in the brain and gastrointestinal tract. We will attempt to alter the pentapeptide structure to make peptides which are antagonistic to the natural occurring material. We propose to study the effects of these peptides on the effects of stereospecific binding of dihydromorphine in brain, on the isolated guinea pig ileum preparation, as well as to place these substances into various regions of the brain and study narcotic agonist properties and dependence liability. Our dependence studies will involve the perfusion of rat brain ventricles with peptides. We are currently using this method in our labs. We will also synthesize radiolabeled peptides to study directly their stereospecific binding to opiate receptors and their distribution in the brain. We will study the distribution and metabolism of the natural pentapeptides as well as that of the more interesting synthetic peptides. This last aspect of the work will be done by Dr. McKelvy and will involve a radioimmune assay technique worked out in his laboratory. Finally, we will investigate the possible interaction with, or effect of the natural occurring and synthetic petides on the neurotransmitter systems of the brain.